SH2 domain-containing inositol 5-phosphatase (SHIP2) inhibition ameliorates high glucose-induced de-novo lipogenesis and VLDL production through regulating AMPK/mTOR/SREBP1 pathway and ROS production in HepG2 cells |
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| Institution: | 1. Department of Pharmacology, College of Basic Medical Sciences, Changchun, Jilin, China;2. Department of Cardiac Surgery, First Hospital of Jilin University, Changchun, Jilin, China;3. Cancer and Stem Cell Center, First Hospital of Jilin University, Changchun, Jilin, China;4. Department of Ultrasonic Cardiogram, First Hospital of Jilin University, Changchun, Jilin, China;5. Stanford University Medical School, VA Palo Alto Health Care System, Palo Alto, California, USA;1. Institute of Pediatric Translational Medicine, Shanghai Children’s Medical Center, Shanghai Jiaotong University School of Medicine, Shanghai 200127, China;2. Department of Neurology, Shanghai Children’s Medical Center, Shanghai Jiaotong University School of Medicine, Shanghai 200127, China;3. Department of Laboratory Medicine, Shanghai Children’s Medical Center, Shanghai Jiaotong University School of Medicine, Shanghai 200127, China;1. DNAGENETIX, Medical Diagnostic Laboratory, Athens, Greece;2. 3rd Department of Pediatrics, University General Hospital « Attikon », University of Athens, Greece;3. 1st Department of Pediatrics, Agia Sofia Hospital, National and Kapodistrian University of Athens, Athens, Greece;4. Pediatric Department, University Hospital of Heraklion, Crete, Greece;5. Pediatric Department, University Hospital of Larissa, University of Thessaly, Larissa, Greece;6. 1st Department of Pediatrics, « Hippokratio » General Hospital, Aristotle University, Thessaloniki, Greece;1. Department of Anatomical Pathology, PathWest Laboratory Medicine, QEII Medical Centre, Nedlands, WA, Australia;2. Translational Cancer Pathology Laboratory, School of Pathology and Laboratory Medicine, The University of Western Australia, Crawley, WA, Australia;1. Department of Toxicology, Bromatology, and Clinical Analysis, University of Sao Paulo, Ribeirao Preto, Brazil;2. Department of Pathology, University of Sao Paulo, Ribeirao Preto, Brazil;1. Human Genome Center, School of Medical Sciences, Universiti Sains Malaysia, Kubang Kerian, Malaysia;2. Center for Neuroscience Services and Research, School of Medical Sciences, Universiti Sains Malaysia, Kubang Kerian, Malaysia;3. Department of Pediatrics, School of Medical Sciences, Universiti Sains Malaysia, Kubang Kerian, Malaysia;4. Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, Serdang, Malaysia;5. Hospital Kuala Lumpur, Kuala Lumpur, Malaysia;6. Hospital Sultanah Aminah, Johor Bahru, Malaysia;7. Hospital Raja Perempuan Zainab II, Kota Bharu, Malaysia;11. Advanced Medical and Dental Institute, Universiti Sains Malaysia, Bertam, Malaysia;12. Division of Human Biology, School of Medicine, International Medical University, Kuala Lumpur, Malaysia |
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| Abstract: | Hepatic de-novo lipogenesis and production of triglyceride rich very low density lipoprotein (VLDL) is increased in the state of insulin resistance, however, the role of a negative regulator of the insulin signaling pathway, the SH2 domain-containing inositol 5-phosphatase (SHIP2) in this process, remains unknown. In the present study, we studied the molecular mechanisms linking SHIP2 expression to metabolic dyslipidemia using overexpression or suppression of SHIP2 gene in HepG2 cells exposed to high glucose (33 mM). The results showed that high glucose induced SHIP2 mRNA and protein levels in HepG2 cells. Overexpression of the dominant negative mutant SHIP2 (SHIP2-DN) ameliorated high glucose-induced de-novo lipogenesis and secretion of apoB containing lipoprotein in HepG2 cells, as demonstrated by a reduction in both secreted apoB and MTP expression, and decreased triglyceride levels and the expression of lipogenic genes such as SREBP1c, FAS and ACC. Overexpression of the SHIP2-DN decreased high glucose-induced apoB containing lipoproteins secretion via reduction in ROS generation, JNK phosphorylation and Akt activation. Furthermore, using the specific inhibitor and activator, it was found that the AMPK/mTOR/SREBP1 is the signaling pathway that mediates the effects of SHIP2 modulation on hepatic de-novo lipogenesis. Taken together, these findings suggest that SHIP2 is an important regulator of hepatic lipogenesis and lipoprotein secretion in insulin resistance state. |
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| Keywords: | De-novo lipogenesis VLDL SH2 domain containing inositol 5-phosphatase (SHIP2) Insulin resistance Hyperglycemia HepG2 Liver |
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